Chx c c



United States Patent 2,815,388 PREPARATION OF AN UNSATURATED C DIOL Hans Herlolf Inholfen, Braunschweig, Germany, and Otto Isler, Marc Montavon, and Rudolf Riiegg, Base], and Paul Zeller, Neuallschwil, Switzerland, assignors to Hotimann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application March 7, 1955, Serial No. 492,748

Claims priority, application Switzerland March 12, 1954 Claims. (Cl. 260-617) This invention relates to an improvement in the preparation of an unsaturated C diol, viz. 1,18-di-(2,6,6-trimethyl 1 cyclohexen l-yl)-3,7,12,l6-tetramethyl-2,4,6, l2,14,l6-octadecahexaen-9-yne-8,ll-diol. This diol is an intermediate in a known synthesis of B-carotene, the latter of course being a compound of known utility. An important object of the invention is an improvement in the synthesis of fi-carotene, more particularly in the preparation of the unsaturated C diol intermediate by a process which is economical and readily adaptable to practice on a commercial scale.

Briefly, the invention relates to a process for preparing 1,18 di (2,6,6 trimethyl-l-cyclohexen-l-yl)-3,7,12,16- tetramethyl 2,4,6,12,l4,16 octadecahexaen 9-yne-8,11- diol which comprises condensing the known compound 8-(2,6,6 trimethyl-l-cyclohexen-1-yl)-2,6-dimethyl-2,4,6- octatrien-l-al in liquid ammonia with an alkali metal acetylide or an alkaline earth metal acetylide, and further condensing the condensation product formed (preferably after hydrolysis of the latter to 10(2,6,6-trimethyl-lcyclohexen l-yl)-4,8-dimethyl-4,6,B-decatrien-l-yn-3-ol) with 8 -(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,6-dimethyl- 2,4,6-octatrien-1-al by means of a metal-organic reaction.

In one comprehensive embodiment, the invention provides a process of making 1,18-di(2,6,6-trimethyl-l-cyclohexen l-yl)-3,7,12,l6-tetramethyl-2,4,6,12,14,16-octaclecahexaen-9-yne-8,1l-diol which comprises the steps of condensing 8 (2,6,6 trimethyl l-cyclohexen-1-yl)2,6- dimethyl-2,4,6-octatrien-l-al with a compound selected from the group consisting of alkali metal acetylides and alkaline earth metal acetylides, hydrolyzing the condensation product thereby producing l0-(2,6,6trimethyl-lcycloheXen l yl)-4,8-dimethyl-4,6,8-decatrien-l-yn-3-ol, reacting the latter with an organometal compound selected from the group consisting of hydrocarbon-magnesiumhalide and hydrocarbon-alkali metal compounds, condensing the di-metal compound obtained with 8-(2,6,6-trimethyl 1 cyclohexen-l-yl)-2,6-dimethyl-2,4,6-octatrienl-al, and hydrolyzing the condensation product thereby producing 1,18 di (2,6,6-trimethyl-l-cyclohexen-l-yD- 3,7,12,16 tetramethyl 2,4,6,12,14,16-octadecahexaen-9- yne-8,l l-diol.

The first stage of the comprehensive embodiment referred to above comprises condensing 8-(2,6,6-trimethyll cyclohexen 1-yl)-2,6-dimethyl-2,4,6-octatrien-l-al in liquid ammonia with an alkali metal acetylide, e. g. sodium acetylide or lithium acetylide, or with an alkaline earth metal acetylide, e. g. calcium acetylide. The condensation can be effected in liquid ammonia either at room temperature under superatmospheric pressure or at the boiling temperature of the ammonia under normal pressure. The acetylide can be prepared from an alkali metal or an alkaline earth metal and acetylene before the condensa- I 2,815,388 Patented Dec. 3, 1957 tion reaction, advantageously in the same vessel and using the same liquid ammonia medium as is to be employed for the condensation. Preferably, lithium acetylide is densation product can be represented by the formula (I) OH: CH

The 8 (2,6,6-trirnethyl-l-cyclohexen-1-yl)-2,6-dimethyl- 2,4,6-octatn'en-1-al can be added as a solution thereof in an inert solvent, as for example diethyl ether. When approximately equimolar proportions of 8-(2,6,6-trimethyl l-cyclohexen-l-yl)-2,6-dimethyl-2,4,6-octatrien- 1-211 and lithium acetylide are employed in the condensation, the yield is almost quantitative. An excess of the acetylide, however, does not influence the reaction unfavorably. Side reactions are substantially absent.

In a second stage of the comprehensive embodiment referred to above, the condensation product obtained in the above described first stage is hydrolyzed, thereby yielding 10-(2,6,6trimethy1 1 cyclohexen-l-yl)-4,8-dimethyl-4,6,8-decatrien-1-yn-3-ol. The hydrolysis can be effected by methods known per se, for example by removing the ammonia from the reaction mixture containing the condensation product and treating the residue with a dilute aqueous solution of a mineral acid. A preferred mode of execution comprises treating the condensation product of the first stage, while still dissolved in liquid ammonia, with an ammonium salt, e. g. ammonium chloride.

The third stage of the comprehensive embodiment referred to above comprises the condensation of the carbinol 10-(2,6,6-trimethyl-l-cyclohexen-l-yl)-4,8-dimethyl- 4,6,8-decatrien-l-yn-3-ol with an organometal compound, e. g. a hydrocarbon-magnesium-halide or a hydrocarbonalkali metal compound, preferably a lower alkyl-magnesium-bromide or -chloride, or a lithium-aryl such as lithium-phenyl. It is advantageous to perform this condensation in an organic solvent, for example a di-lower alkyl ether such as diethyl ether. Approximately two mols of the organometal compound are employed for each mol of carbinol. The first mol of the metal compound reacts with the hydroxyl group in the carbinol, whereas the second mol substitutes the hydrogen of the acetylenic linkage and renders the terminal carbon atom of the carbinol reactive in the succeeding condensation reaction of the fourth stage, described below. The dimagnesium-halide or di-alkali metal compound thus obtained as the condensation product can be represented by wherein M represents a monovalent radical selected from the group consisting of -Mg-halide and alkali metal.

In the fourth stage of the comprehensive process, said condensation product II is reacted (advantageously in the same organic solvent in which it was prepared) with 8-(2,6,6-trimethyl-l-cyclohexen-1-yl)-2,6 dimethyl-2,4,6- octatrien-l-al. For purposes of further reaction it is unnecessary (indeed, it is preferred not) to isolate or CH3 CH3 determination showed 1 atom of active hydrogen in the cold and 2 atoms when warm.

CH; CH;

HI H: C H;

wherein M has the same meaning as in Formula II above. The final stage in the comprehensive embodiment referred to above comprises hydrolyzing said condensation product III. As indicated, this operation is preferably carried out directly upon formation of product Ill, by methods known per se, for example by pouring the solution containing said condensation product onto a mixture of ice and dilute aqueous sulfuric acid. In the case of a Grignard reaction, i. e. when M represents -Mg-halide. the yield of C -diol obtained is practically quantitative.

in a further embodiment of the invention, different from that described above, approximately one molar proportion of an alkali metal amide, e. g. sodamide or lithium amide, is added to a suspension in liquid ammonia of the condensation product I obtained by condensing 8-(2,6,6- trimethyl l cyclohexen-1-yl)-2,6-dimethyl 2,4,6-octatrien-l-al with lithium acetylide, and thereupon an additional molar proportion of 8-(2,6,6-trimethyl-l-cyclohexen l yl) 2,6 dimethyl 2,4,6 octatrien 1 a1 is added to the liquid ammonia containing the condensation product (Formula II above, wherein each M represents an alkali metal). Upon hydrolysis of the resulting C condensation product (Formula III above, wherein each M represents an alkali metal), 1,l8-di-(2,6,6-trimethyll cyclohexcn 1 yl) 3,7,12,16 tetramethyl 2,4,6,12,14, l6-octadecahexaen9-yne-8,1l-diol is obtained directly.

A preferred mode of practicing the invention comprises condensing 8-( 2.6,6-trimcthyll-cyclohexen-l-yl) -2,6-dimethyl-2,4,6-octatrien-l-al in liquid ammonia with an ap proximately equimolar proportion of lithium acetylide, treating the condensation product in liquid ammonia with an ammonium salt, removing the ammonia from the 10- (266 trimethyl 1 cyclohcxen 1 yl) 4,8 dimethyl- 4,6.8-decatrien-l-yn-3-ol formed, reacting the latter in a di-lower alkyl ether (preferably diethyl ether) with approximately two molar proportions of a lower alkyl magnesium halide (preferably ethyl magnesium bromide), condensing the dimagnesium-halide compound obtained with 8 (2,6,6 trimethyl 1 cyclohexen 1 yl) 2,6- dimethy1'2,4,o-octatrien-l-al, and hydrolyzing the condensation product thereby producing l,lS-di-(2,6,6-trimethyl 1 cyclohexen l yl) 3,7,12,16 tetramethyl- 2,4,6, 12, l4,16'octadecahexaen-9-yne-8,l l-diol.

The invention is further disclosed in the following example, which is illustrative but not limitative thereof:

Example Dry. acetone-free acetylene was introduced into a solution of 1.7 g. of lithium in 600 cc. of liquid ammonia until the color disappeared, and for an additional period of 30 minutes thereafter to complete the reaction. Then, over a period of minutes and while stirring vigorously. a solution of 59 g. of 8-(2,6,6-trimethyl-l-cyclohexen-1- yl) -2,6-dimethyl-2,4,6-octatrien-l-al in 200 cc. of absolute diethyl ether was added. The reaction mixture was stirred thoroughly for hours while excluding moisture. At the end of this time 20 g. of ammonium chloride was added portionwise and then the ammonia was evaporated ofi. 200 cc. of water was added, the ether layer was separated, washed with water, dried over sodium sulfate and concentrated. The residual light yellow oil was thoroughly dried in vacuo. There was obtained 64.2 g. of 10 (2,6,6 trimethyl 1 cyclohexen l yl) 4,8 dimethyl 4.6.8 decatrien 1 yn 3 o1, n =1.576; U. V. max. 280-1 ma, E =1630 in petroleum ether. The yield was precticellv antitative, A Zerewitinoff 3-01 in 200 cc. of absolute diethyl ether.

To a Grignard solution prepared from 11.5 g. of magnesium chips, 37 cc. of ethyl bromide and cc. of absolute diethyl ether was added slowly at 15-20" C., while stirring and cooling, a solution of 64.2 g. of l0-(2,6,6-trimethyl 1 cyclohexen 1 yl) 4,6,8 decatrien l yn- The reaction mixture was refluxed for one hour in a nitrogen atmosphere and was then. cooled down with ice water. A solw tion of 58.9 g. of 8-(2,6,6-trimethyl-l-cyclohexen-l-yl)- 2,6-dimethyl-2,4,6-octatrienl-al in 300 cc. of absolute diethyl ether was added at about 20 C.. and then the reaction mixture was refluxed for about 4 hours in a nitrogen atmosphere. The reaction mixture was then poured onto a mixture of 200 cc. of 3N aqueous sulfuric acid and 300 g. of ice, the whole was diluted with 3000 cc. of diethyl ether and shaken well for a few minutes. The ether layer was separated, washed with 5 percent aqueous sodium bicarbonate solution. dried over sodium sulfate and concentrated in vacuo at about 40 C. There was thus obtained 123 g. of l,l8-di-(2,6,6-trimethyl-Lcyclohexen-I- yl) 3,7,12,16 tetramethyl 2,4,6,l2,l4.l6 OClZtdiiClthexaen 9 yne 8,11 die] as a crystallinc residue. U. V. max., 280-]. m 5: 87000 in petroleum ether; active hydrogen: 2.0 (cold). Yield: almost quantitative. The product can be recrystallized from petroleum ether, if desired.

We claim:

1. A process which comprises condensing 8-(2,6,6-trimethyl 1 cyclohexcn l yl) 2,6 dimethyl 2.4.6- octatrien 1 2:1 with a compound selected from the group consisting of alkali metal acctylidcs and alkaline earth metal acetylides, hydrolyzing the condensation product thereby producing 10 (2,6,6 trimethyl 1 CYClOl'lC'itlL l yl) 4,8 dimethyl 4,6,8 decatricn l yn 3 ol. reacting the latter with an organometal compound selected from the group consisting of hydrocarboiwnapn dumhalide and hydrocarbon-alkali metal compounds, condensing the (ii-metal compound obtained with 8-(2.r3.e-trimethyl 1 cyclohexen l yl) 2,6 dimethyl 2,4,6- octatrien l al, and hydrolyzing the condensation prod uct thereby producing 1.18 di (2,6.6 trimethyl 1- cyclohexen l yl) 3,7,12,16 tetramethyl 2.4.6.1214. l6-octadecahexaen-9-y11e-8, l l-diol.

2. A process which comprises condensing 8-(2.6.6trimethyl 1 cyclohesen l yl) 2.6 dimethyl 2,4,6- octatrien-l-al in liquid ammonia with a compound selected from the group consisting of alkali metal acctylides and alkaline earth metal acetylides and hydrolyzing the condensation product thereby producing lU-(2,6,6-trimethyl l cyclohexen 1 yl) 4,8 dimethyl 4,6,8- decatrien-l-yn-B-ol.

3. 10 (2,6,6 trimethyl 1 cyclohexen 1 yl) 4,8- dimethyl-4,6,8-decatrien-1-yn-3-ol.

4. The compound CHI CH1 5. A process which comprises condensing 8-(2,6,6-trimethyl 1 cyclohexen 1 yl) 2,6 dimethyl 2,4,6-

octatrien-l-al with lithium acetylide in liquid ammonia, dimethyl-2,4,6-octatrien-l-al in an organic solvent, therethereby producing a compound according to claim 4. by producing a compound having the formula CH3 H30 6. A compound having the formula 10. A process which comprises condensing 8 (2,6,6 CH3 CH3 trimethyl 1 cyclohexen l yl) 2,6 dimethyl -2,4,6 M octatrien-l-al in liquid ammonla with an approx1mate1y OHFCH=(; CH=CH CH=C (BH GEO M equimolar proportion of lithium acetylide, treating the condensation product in liquid ammonia with an ammo- H3 nium salt, removing the ammonia from the l0-(2,6,6-trimethyl 1 cyclohexen l yl) 4,8 dimethyl 4,6,8

wherein M represents a member l t d f h group decatrien-1yn-3-ol formed, reacting the latter in an organic consisting of Mg ha1ide d alk li t l, solvent with approximately two molar proportions of a 7. A process which comprises condensing 10-(2,6,6, lower alkyl magnesium halide, condensing the di-magtrimethyl l cyclohexen 1 yl) 4,8 dimethyl 4,6,8 2 nesium-halide compound obtained with 8-(2,6,6-trimethyldecatrien-l-yn-3-ol with an organometal compound se- 0 y -Y i y Afiand lected from the group consisting of hydrocarbon-maghydmlyling the Cofldmsaiion Product thereby Producing nesium-halide and hydrocarbon-alkali metal compounds, di tl'imflhyl 1 cyclohexell 1 Y thereby producing a compound according to claim 6. tetl'flmethyl 2,4,6,12,14,16 OctadecaheXaen 8. A process which comprises condensing a compound -Y J having the formula References Cited 1n the file of th1s patent CH CH UNITED STATES PATENTS CH2-CH=C-CH=OHCH=G7H-CECM 2,369,164 Milas Feb. 13, 1945 A 5 2,671,112 Inhoffen et al Mar. 2, 1954 CH3 2,674,621 Oroshnik Apr. 6, 1954 wherein M represents a member selected from the group OTHER REFERENCES consisting of -Mghalide and alkali metal, with 8-(2,6,6- Tome: Synthesis and Allylic Rearrangement of 1-(2- trimethyl l cyclohexen l yl) 2,6 dimethyl 2,4,6 Methylcyclohexene 1 yl) 3 Methylpent 4 En 1 octatrien-l-al, and hydrolyzing, thereby producing 1,18- Yn-3-Ol. Thesis at Mass. Inst. Tech., May 23, I947 di (2,6,6 trimethyl 1 cyclohexen 1 yl) 3,7,12,16 (28 pp.). tetramethyl 2,4,6,12,14,l6 octadecahexaen 9 yne Karrer et al.: Helv. Chim. Acta., vol. 34 (1951), pp. 8,11-diol. 28-33 (6 pp.).

9. A process which comprises condensing 'a compound 40 having the formula with 8- (2,6,6-ttimethy1- 1 -cyclohexen- 1 -yl) -2, 

10. A PROCESS WHICH COMPRISES CONDENSING 8 (2,6,6TRIMETHYL -1- CYCLOHEXEN- 1- YL)-2,5- DIMETHYL-2,4,6OCTATRIEN-1-AL IN LIQUID AMMONIA WITH AN APPROXIMATELY EQUIMOLAR PROPOTION OF LITHIUM ACETYLIDE, TREATING THE CONDENSATION PRODUCT IN LIQUID AMMONIA WITH AN AMMONIUM SALT, REMOVING THE AMMONIA FROM THE 10-(2,6,6-TRIMETHYL- 1- CYCLOHEXEN - 1 -YL) -4,8-DIMETHYL- 4,6,8DECATRIEN-LYN-3-OL FORMED, REACTING THE LATTER IN AN ORGANIC SOLVENT WITH APPROXIMATELY TWO MOLAR PORPORTIONS OF A LOWR ALKYL MAGNESIUM HALIDE, CONDENSING THE DI-MAGNESIUM-HALIDE COMPOUND OBTAINED WITH 8-(2,6,6-TRIMETHYL1-CYCLOHEXEN-1-YL)-2,6-DIMETHYL-2,4,6-OCTATRIEN-1-AL, AND HYDROLYZING THE CONDENSATION PRODUCT THEREBY PRODUCING 1,18 -DI- (2,6,6 -TRIMETHYL- 1- CYCLOHEXEN- 1-YL)3,7,12,16- TETRAMETHYL -2,4,6,12,14,16 - OCTADECAHEXAEN 9-YNE-8,11-DIOL. 